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Katherine Lafferty

Katherine Lafferty

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Disease

Diamond-Blackfan anemia 14 with mandibulofacial dysostosis

Inheritance

X-linked

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 Overall incidence of Diamond-Blackfan 5-7 per million

Source: https://medlineplus.gov/genetics/condition/diamond-blackfan-anemia/

Rapid or full curation?

  •  Rapid
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Not in ClinGen (In Scope for General GCEP and CAYA GCEP)

GenCC- XL Diamond-Blackfan anemia 14 with mandibulofacial dysostosis (Limited- Invitae)

OMIM- ?Diamond-Blackfan anemia 14 with mandibulofacial dysostosis XL

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

PMID 24942156- Variant (c.191A>G p.Glu64Gly) in one male with features of Diamond-Blackfan anemia and facial features suggestive of Treacher Collins. This variant was also found in an male cousin with facial features but no overt features of Diamond-Blackfan but was reported to have “elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers” by age 16. This segregation is through three unaffected females. Family previously described in PMID: 11424144 (0.5 pts)

PMID 30503522- The same c.191A>G p.Glu64Gly was identified in two related individuals with DBA through WES (0.5 pts)

Segregation Evidence:

Case/Control Evidence:

Experimental Evidence:

PMID 30201955- Functional study in yeast cells with the E64G variant noted above showed impact to protein function (1 pt)

PMID 29551269- Functional studies show impact mutations in TRS2; some studies seem to be a repeat of above.

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Limited

Source:

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

Penetrance

Expand
titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

Expand
titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

Expand
titleOptions

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

Expand
titleExamples

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

Case ID, Curator name, Date, Jira ticket link

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